The present invention relates to the discovery, identification, and characterization of novel human polynucleotides encoding proteins that share sequence similarity with animal gamma-amino butyric acid (GABA) receptor subunits. The invention encompasses the described polynucleotides, host cell expression systems, the encoded proteins, fusion proteins, polypeptides and peptides, antibodies to the encoded proteins and peptides, and genetically engineered animals that either lack or over express the disclosed sequences, antagonists and agonists of the proteins, and other compounds that modulate the expression or activity of the proteins encoded by the disclosed sequences that can be used for diagnosis, drug screening, clinical trial monitoring and the treatment of diseases and disorders.
Membrane proteins play important roles as, inter alia, cell surface markers, receptors, and mediators of signal transduction. GABA receptors bind a potent inhibitory neurotransmitter and this interaction serves as a target for a variety of pharmaceutical agents such as benzodiazepines, barbiturates and alcohol.
The present invention relates to the discovery, identification, and characterization of nucleotides that encode novel human proteins, and the corresponding amino acid sequences of these proteins. The novel human proteins (NHPs) described for the first time herein share structural similarity with membrane receptors such as, but not limited to human and other mammalian GABA receptors.
The novel human nucleic acid sequences described herein, encode alternative proteins/open reading frames (ORFs) of 467, 392, 180, 420, 345, and 133 amino acids in length (see SEQ ID NOS: 2, 4, 6, 8, 10, and 12 respectively).
The invention also encompasses agonists and antagonists of the described NHPs, including small molecules, large molecules, mutant NHPs, or portions thereof that compete with native NHP, peptides, and antibodies, as well as nucleotide sequences that can be used to inhibit the expression of the described NHPs (e.g., antisense and ribozyme molecules, and gene or regulatory sequence replacement constructs) or to enhance the expression of the described NHP sequences (e.g., expression constructs that place the described sequence under the control of a strong promoter system), and transgenic animals that express a NHP transgene, or xe2x80x9cknock-outsxe2x80x9d (which can be conditional) that do not express a functional NHP. A gene trapped murine ES cell line has been produced that knocks-out a murine ortholog of the described NHPs.
Further, the present invention also relates to processes for identifying compounds that modulate, i.e., act as agonists or antagonists, of NHP expression and/or NHP activity that utilize purified preparations of the described NHPs and/or NHP product, or cells expressing the same. Such compounds can be used as therapeutic agents for the treatment of any of a wide variety of symptoms associated with biological disorders or imbalances.